Metformin inhibits growth of lung adenocarcinoma cells by inducing apoptosis via the mitochondria-mediated pathway

Wang, Junling; Gao, Qiuling; Wang, Decui; Wang, Zhiqiang; Hu, Chun

doi:10.3892/ol.2015.3450

Cited by 40 publications

(33 citation statements)

References 28 publications

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“…Metformin, which is a member of the biguanide family, is predominantly used for the treatment of type 2 diabetes by increasing insulin sensitivity (13). Recently, epidemiologists discovered that diabetic patients who were treated with metformin had a lower risk, and lower incidence, of multiple types of cancer (14,15).…”

Section: Introductionmentioning

confidence: 99%

Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in�vitro and in�vivo

Chen

et al. 2018

Oncol Rep

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Hypoxia plays a crucial role in cancer development and progression. Overexpression of hypoxia-inducible factor-1α (HIF-1α) has been demonstrated in a hypoxic microenvironment in various tumor types. Metformin has been identified as an antitumor drug in various tumor types. However, its role in cellular migration in a hypoxic microenvironment, and the associated regulatory mechanism, have yet to be fully elucidated. The present study aimed to investigate the clinical significance of HIF-1α, and its biological role, in gallbladder cancer (GBC). Furthermore, the role of metformin in cellular migration, and its underlying mechanism in GBC, were also identified. Real-time quantitative polymerase chain reaction analysis and immunohistochemistry experiments revealed that HIF-1α was significantly upregulated in GBC tissues. HIF-1α overexpression was closely associated with lymph node metastasis and tumor-lymph node-metastasis (TNM) stages. HIF-1α was able to promote cell migration in a hypoxic microenvironment by overexpressing vascular endothelial growth factor (VEGF) in GBC-SD cells, an effect which was partly reversed by small-interfering RNA HIF-1α (siHIF-1α) and 2-methoxyestradiol. Further experiments demonstrated that metformin inhibited hypoxia-induced migration via HIF-1α/VEGF in vitro. In addition, metformin suppressed GBC growth and downregulated the expression of HIF-1α and VEGF in a GBC-SD cell xenograft model. Taken together, these results suggest that HIF-1α may contribute to tumor migration via the overexpression of VEGF in GBC, while metformin is able to inhibit tumor migration by targeting the HIF-1α/VEGF pathway.

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Section: Introductionmentioning

confidence: 99%

Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in�vitro and in�vivo

Chen

et al. 2018

Oncol Rep

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“…It is well established that metformin could inhibit cell proliferation in several cancer cells in vitro [5–7]. However, the effect and mechanism of metformin on cell proliferation in some certain cancer cells remain poorly understood.…”

Section: Resultsmentioning

confidence: 99%

Metformin Induces Growth Inhibition and Cell Cycle Arrest by Upregulating MicroRNA34a in Renal Cancer Cells

et al. 2017

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BackgroundMetformin is a widely used biguanide drug for the treatment of type 2 diabetes. It has been revaluated as a potential anti-cancer drug with promising activity in various tumors. However, the precise mechanisms underlying the suppression of cancer cells by metformin remain not well understood.Material/MethodsIn this study, human renal cell carcinoma cell line ACHN was used to investigate the anti-proliferation effect of metformin. A cell counting kit-8 assay was used to detect the cell viability. The cell cycle distribution and apoptosis were analyzed by flow cytometry. The expression of cyclin D1 and p27KIP1 was detected by Western blot. The underlying mechanism involving miRNA34a was further investigated by quantitative RT-PCR and transfection with miRNA inhibitor specific for miRNA34a in ACHN, 769-P, and A498 cells.ResultsMetformin could significantly inhibit the proliferation of ACHN cells in a dose- and time-dependent manner. In addition, the results showed that metformin induced G0/G1 phase arrest and delayed entry into S phase in ACHN cells. It was shown that metformin downregulates the expression of cyclin D1 and increases the p27KIP1 level. Furthermore, metformin increased ACHN cell death. Lastly, miRNA34a was found to be upregulated by metformin in ACHN, 769-P, and A498 cells. Subsequently, it was demonstrated that inhibition of miRNA34a could partially attenuate the suppressive effect of metformin on renal cancer cell proliferation.ConclusionsThe study data revealed that metformin induced cell growth inhibition and cell cycle arrest partially by upregulating miRNA34a in renal cancer cells.

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“…Relative to tumor size in vivo after treatment with metformin, Wang et al [51], demonstrated that xenograft tumor from lung adenocarcinoma A549 cells treated with metformin (200 mg/kg/day) was signifiantly decreased in size. The same was observed in a study of Tsutsumi et al [52] that showed a tumor volume significantly decreased after treatment with metformin compared with the control in animal xenografic model with prostate cancer cell line LNCaP.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Epithelial-Mesenchymal Transition and Metastasis by Combined TGFbeta Knockdown and Metformin Treatment in a Canine Mammary Cancer Xenograft Model

Leonel

Borin

Ferreira

et al. 2017

J Mammary Gland Biol Neoplasia

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Epithelial mesenchymal transition (EMT) is a process by which epithelial cells acquire mesenchymal properties, generating metastases. Transforming growth factor beta (TGF-β) is associated with this malignancy by having the ability to induce EMT. Metformin, has been shown to inhibit EMT in breast cancer cells. Based on this evidence we hypothesize that treatment with metformin and the silencing of TGF-β, inhibits the EMT in cancer cells. Canine metastatic mammary tumor cell line CF41 was stably transduced with a shRNA-lentivirus, reducing expression level of TGF-β1. This was combined with metformin treatment, to look at effects on cell migration and the expression of EMT markers. For in vivo study, unmodified or TGF-β1sh cells were injected in the inguinal region of nude athymic female mice followed by metformin treatment. The mice's lungs were collected and metastatic nodules were subsequently assessed for EMT markers expression. The migration rate was lower in TGF-β1sh cells and when combined with metformin treatment. Metformin treatment reduced N-cadherin and increased E-cadherin expression in both CF41 and TGF-β1sh cells. Was demonstrated that metformin treatment reduced the number of lung metastases in animals bearing TGF-β1sh tumors. This paralleled a decreased N-cadherin and vimentin expression, and increased E-cadherin and claudin-7 expression in lung metastases. This study confirms the benefits of TGF-β1 silencing in addition to metformin as potential therapeutic agents for breast cancer patients, by blocking EMT process. To the best of our knowledge, we are the first to report metformin treatment in cells with TGF-β1 silencing and their effect on EMT.

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Metformin inhibits growth of lung adenocarcinoma cells by inducing apoptosis via the mitochondria-mediated pathway

Cited by 40 publications

References 28 publications

Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in�vitro and in�vivo

Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in�vitro and in�vivo

Metformin Induces Growth Inhibition and Cell Cycle Arrest by Upregulating MicroRNA34a in Renal Cancer Cells

Inhibition of Epithelial-Mesenchymal Transition and Metastasis by Combined TGFbeta Knockdown and Metformin Treatment in a Canine Mammary Cancer Xenograft Model

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